- p62-mediated autophagy affects nutrition-dependent insulin receptor substrate-1 dynamics in 3T3-L1 preadipocytes. [Journal Article]
- JDJ Diabetes Investig 2018 May 22
- CONCLUSIONS: Autophagy through p62 plays an important role in regulating IRS-1 protein levels in response to nutritional deficiency. Our findings suggest that autophagy may function as energy depletion-sensing machinery that finely tunes insulin signal transduction. This article is protected by copyright. All rights reserved.
- Antimalarial Activity of Stem Bark of Periploca linearifolia during Early and Established Plasmodium Infection in Mice. [Journal Article]
- EBEvid Based Complement Alternat Med 2018; 2018:4169397
- CONCLUSIONS: The plant Periploca linearifolia has a promising antimalarial activity in mice, supporting its in vitro finding. Thus, it could be considered as a potential source to develop new antimalarial agent.
- Silibinin Induced Human Glioblastoma Cell Apoptosis Concomitant with Autophagy through Simultaneous Inhibition of mTOR and YAP. [Journal Article]
- BRBiomed Res Int 2018; 2018:6165192
- Silibinin, also known as silybin, is the major flavonolignan isolated from Silybum marianum. Although previous reports demonstrated that silibinin exhibits significant tumor suppressor activities in ...
Silibinin, also known as silybin, is the major flavonolignan isolated from Silybum marianum. Although previous reports demonstrated that silibinin exhibits significant tumor suppressor activities in various cancers by promoting cell apoptosis, it was also shown to trigger autophagy to counteract apoptosis induced by exogenous stresses in several types of cells. However, there is no report to address the role of silibinin induced autophagy in human A172 and SR glioblastoma cells. Our study showed that silibinin treatment not only inhibited the metabolic activities of glioblastoma cells but also promoted their apoptosis through the regulation of caspase 3 and PARP-1 in concentration- and time-dependent manners. Meanwhile, silibinin induced autophagy through upregulation of microtubule-associated protein a light chain 3- (LC3-) II. And autophagy inhibition with chloroquine, a lysosomotropic agent, significantly enhanced silibinin induced glioblastoma cell apoptosis. Moreover, silibinin dose-dependently downregulated the phosphorylation levels of mTOR at Ser-2448, p70S6K at Thr-389, and 4E-BP1 at Thr-37/46. Furthermore, the expression of YAP, the downstream effector of Hippo signal pathway, was also suppressed by silibinin. These results suggested that silibinin induced glioblastoma cell apoptosis concomitant with autophagy which might be due to simultaneous inhibition of mTOR and YAP and silibinin induced autophagy exerted a protective role against cell apoptosis in both A172 and SR cells.
- Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis. [Journal Article]
- CLCancer Lett 2018 May 16
- Suppressing glutaminolysis does not always induce cancer cell death in glutamine dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we...
Suppressing glutaminolysis does not always induce cancer cell death in glutamine dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis in cancer cells. Glutaminolysis inhibition with C.968 suppressed cell proliferation but was insufficient to induce cancer cell death. We found that lipid catabolism was activated as a compensation for glutaminolysis inhibition. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. Simultaneously inhibiting glutaminolysis and either beta oxidation with trimetazidine or autophagy with chloroquine both induced cancer cell death. Here we identified metabolic escape mechanisms contributing to cancer cell survival under treatment and we suggest potentially translational strategy for combined cancer therapy, given that chloroquine is an FDA approved drug. Our findings are first to show efficiency of combined inhibition of glutaminolysis and beta oxidation as potential anti-cancer strategy as well as add to the evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.
- Anti-plasmodial activities of Combretum molle (Combretaceae) [Zwoo] seed extract in Swiss albino mice. [Journal Article]
- BRBMC Res Notes 2018 May 18; 11(1):312
- Objective of the study was to evaluate in vivo anti-plasmodial activities of Combretum molle seed extract.
Objective of the study was to evaluate in vivo anti-plasmodial activities of Combretum molle seed extract.
- Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy. [Journal Article]
- OOncotarget 2018 Apr 24; 9(31):22113-22122
- Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatmen...
Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.
- Inactivated Sendai Virus Induces ROS-dependent Apoptosis and Autophagy in Human Prostate Cancer Cells. [Journal Article]
- BEBiomed Environ Sci 2018; 31(4):280-289
- CONCLUSIONS: HVJ-E exerts anticancer effects via autophagic cell death in prostate cancer cells.
- Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection. [Journal Article]
- VViruses 2018 May 17; 10(5)
- Since 2005, Chikungunya virus (CHIKV) re-emerged and caused numerous outbreaks in the world, and finally, was introduced into the Americas in 2013. The lack of CHIKV-specific therapies has led to the...
Since 2005, Chikungunya virus (CHIKV) re-emerged and caused numerous outbreaks in the world, and finally, was introduced into the Americas in 2013. The lack of CHIKV-specific therapies has led to the use of non-specific drugs. Chloroquine, which is commonly used to treat febrile illnesses in the tropics, has been shown to inhibit CHIKV replication in vitro. To assess the in vivo effect of chloroquine, two complementary studies were performed: (i) a prophylactic study in a non-human primate model (NHP); and (ii) a curative study "CuraChik", which was performed during the Reunion Island outbreak in 2006 in a human cohort. Clinical, biological, and immunological data were compared between treated and placebo groups. Acute CHIKV infection was exacerbated in NHPs treated with prophylactic administration of chloroquine. These NHPs displayed a higher viremia and slower viral clearance (p < 0.003). Magnitude of viremia was correlated to the type I IFN response (Rho = 0.8, p < 0.001) and severe lymphopenia (Rho = 0.8, p < 0.0001), while treatment led to a delay in both CHIKV-specific cellular and IgM responses (p < 0.02 and p = 0.04, respectively). In humans, chloroquine treatment did not affect viremia or clinical parameters during the acute stage of the disease (D1 to D14), but affected the levels of C-reactive Protein (CRP), IFNα, IL-6, and MCP1 over time (D1 to D16). Importantly, no positive effect could be detected on prevalence of persistent arthralgia at Day 300. Although inhibitory in vitro, chloroquine as a prophylactic treatment in NHPs enhances CHIKV replication and delays cellular and humoral response. In patients, curative chloroquine treatment during the acute phase decreases the levels of key cytokines, and thus may delay adaptive immune responses, as observed in NHPs, without any suppressive effect on peripheral viral load.
- Summary of recommendations for the prevention of malaria by the Committee to Advise on Tropical Medicine and Travel (CATMAT). [Journal Article]
- CCCan Commun Dis Rep 2014 Apr 03; 40(7):118-132
- On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Am...
On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill.
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- Autophagy mediates enhancement of proangiogenic activity by hypoxia in mesenchymal stromal/stem cells. [Journal Article]
- BBBiochem Biophys Res Commun 2018 May 14
- Mesenchymal stromal/stem cells (MSCs) have been promising source for regenerative cell therapy in ischemic diseases. To improve efficacy of MSC therapy, various priming methods have been developed, a...
Mesenchymal stromal/stem cells (MSCs) have been promising source for regenerative cell therapy in ischemic diseases. To improve efficacy of MSC therapy, various priming methods have been developed, and hypoxic priming has been reported to enhance therapeutic efficacy of MSCs by increasing secretion level of growth factors and cytokines. Recently, it has been reported that bone marrow MSCs primed with hypoxic condition show an increase of autophagy. Here, we addressed whether proangiogenic activity increased by hypoxic condition is associated with autophagy. Wharton's jelly derived MSCs primed with hypoxia showed increase of autophagy with increased hypoxia inducible factor-1α level, and conditioned medium (CM) derived from these cells showed increased levels of migration and tube formation of human umbilical vein endothelial cells (HUVECs) compared to non-primed MSCs-derived CM. Pretreatment with autophagy inhibitor 3-methyladenine or chloroquine prior to exposure of hypoxia resulted in reduction of migration and tube formation of HUVECs. CM obtained under hypoxic condition from MSCs in which autophagy activity was inhibited by ATG5 and ATG7 siRNA treatment also showed decrease of migration and tube formation of HUVECs. Accordingly, secretion levels of angiogenin and VEGF that were markedly increased upon hypoxia exposure was decreased by ATG5/7 knockdown. Therefore, it may be suggested that autophagy plays an important role in hypoxia-driven enhancement of paracrine effect of MSCs.